Liquiritin targets NF-κB/MAPK signaling to attenuate osteoclastogenesis and triggers apoptosis through PPARγ activation

  • Phytomedicine. 2025 Dec:149:157604. doi: 10.1016/j.phymed.2025.157604.
Jingtao Wu  1 ,  Yuhao Zhang  1 ,  Yipeng Wang  1 ,  Huabin Liu  1 ,  Xiao Sheng  1 ,  Xiongfeng Li  2 ,  Qian Lu  3 ,  Yongli Wang  4
Affiliations
  • 1. Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang 313000, China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang 313000, China; Department of Orthopaedics, Huzhou Central Hospital, Huzhou Basic and Clinical Translation of Orthopaedics Key Laboratory, Huzhou, Zhejiang 313000, China.
  • 2. Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang 313000, China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang 313000, China; Department of Orthopaedics, Huzhou Central Hospital, Huzhou Basic and Clinical Translation of Orthopaedics Key Laboratory, Huzhou, Zhejiang 313000, China. Electronic address: [email protected].
  • 3. Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang 313000, China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang 313000, China; Department of Orthopaedics, Huzhou Central Hospital, Huzhou Basic and Clinical Translation of Orthopaedics Key Laboratory, Huzhou, Zhejiang 313000, China. Electronic address: [email protected].
  • 4. Huzhou Central Hospital, Affiliated Central Hospital of Huzhou University, Huzhou, Zhejiang 313000, China; Huzhou Central Hospital, Fifth School of Clinical Medicine of Zhejiang Chinese Medical University, Huzhou, Zhejiang 313000, China; Department of Orthopaedics, Huzhou Central Hospital, Huzhou Basic and Clinical Translation of Orthopaedics Key Laboratory, Huzhou, Zhejiang 313000, China. Electronic address: [email protected].
PMID: 41308395 DOI: 10.1016/j.phymed.2025.157604
Abstract

Background: Postmenopausal Osteoporosis (PMOP) is an estrogen-deficiency disorder that leads to impaired bone remodeling and a higher incidence of fractures. Liquiritin, a flavonoid from Glycyrrhiza uralensis, has documented bioactivities but previously unexplored potential for PMOP treatment.

Purpose: To investigate liquiritin's therapeutic effects on PMOP and its underlying mechanisms, constituting the first comprehensive investigation of its role in osteoclasts regulation and Apoptosis induction within PMOP pathophysiology.

Methods: Network pharmacology was employed to predict potential targets of Liquiritin in PMOP. The CCK-8 assay assessed its effect on bone marrow-derived macrophages (BMDMs) viability. RANKL was used to induce BMDMs differentiation into mature osteoclasts. TRAcP and F-actin staining detected osteoclasts formation; bone resorption assays evaluated functionality. Western blotting and immunofluorescence were applied to evaluate osteoclasts-related proteins, MAPK/NF-κB pathway activity, and Apoptosis. Notably, molecular docking predicted Liquiritin's binding to PPARγ, validated by CETSA. An OVX-induced PMOP mouse model was constructed in vivo; bone microarchitecture and osteoclasts activity were evaluated using micro-CT, H&E, and TRAcP staining.

Results: Liquiritin suppressed osteoclasts formation and bone resorption in vitroand mitigated bone loss in vivo by downregulating osteoclasts-specific genes, inhibiting MAPK/NF-κB pathways, and most importantly, inducing PPARγ-mediated apoptosis-a novel mechanistic insight not previously reported.

Conclusion: Liquiritin exerts anti-osteoporotic effects by targeting Osteoclastogenesis, inducing Apoptosis, and inhibiting bone resorption via PPARγ activation, highlighting its novel therapeutic potential for PMOP treatment.

Keywords
Apoptosis; Liquiritin; MAPK; NF-κB; Network pharmacology; Osteoclasts; PMOP; PPARγ.
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